A major problem in the treatment of acute leukemia is the development of resistance to chemotherapy and subsequent relapse. Despite classifications that facilitate the assignment of patients into high-risk or standard-risk groups, there is no way at the present time to determine when and which of these patients will become resistant to drug-treatment. The ability to predict accurately this lack of response to oncolytic agents would seem to be of much clinical utility. The primary objective of this grant proposal is to develop a prototype of a sensitive microdetection assay for the presence of small number of drug-resistant cells in heterogeneous populations containing primarily sensitive cells. The proposed assay will differ from its predecessors in that it will be based solely on phenotypic differences between sensitive and drug-resistant cells. This assay will not only be independent of cell growth and cell culture, but it will also be independent of traditional metabolic parameters such as the activity of "target" enzymes and the uptake or incorporation of drugs and precursors of macromolecules. The detection of drug-resistant cells will require a biochemical characterization of resistance-associated molecular changes, as determined by high-resolution analytical methods; detection will be based on immunofluorescent technics employing flow cytometry, as well as radioimmunoassay. The long-term goal of such proposed research is to develop a battery of these tests that may have ultimate clinical utility by facilitating the individualization of therapy. It is further anticipated that new knowledge about the molecular biology of drug-resistance will be obtained through these studies.